We have developed a chemotherapy regimen (EPOCH) which employs standard drugs for the treatment of recurrent lymphomas but administers the natural products (doxorubicin, vincristine and etoposide) as a 96 hour continuous infusion. The rationale for this approach is based on the in vitro finding that tumor cells exposed to natural products at low doses for prolonged periods are more sensitive then when exposed to high doses for short periods. The trial has two objectives. The first was to assess the efficacy and toxicity of EPOCH in patients with relapsed lymphomas. The results of this study showed that EPOCH was well tolerated with an overall response rate of 80%. The second goal was to assess the therapeutic efficacy of R-verapamil with EPOCH chemotherapy in those patients who had progressive or stable disease while receiving EPOCH alone; R-verapamil is a competitive inhibitor of the p-170 pump, the mechanism of multidrug resistance. Sixty-six patients have crossed over to receive R-verapamil of which 5 were not evaluable for response; 68% were male and the median age was 48 years. Histologies included non-Hodgkin's lymphomas in 85% and Hodgkin's disease in 15% of patients. Of the 10 patients with Hodgkin's disease, one achieved a partial response and three achieved minor responses. Of 47 patients with non-Hodgkin's lymphomas, there were 2 CRs, 9PRs, and 3 MRs; a 23% objective response rate. Pharmacokinetics of R- verapamil and the chemotherapeutic drugs, doxorubicin and etoposide are being measured. Tissue samples for analysis of mdr expression were obtained in 20 patients and expression will be correlated with response to R-verapamil. This trial is nearing completion.